Psoriasis Vladimír Vašků I. dermatovenerologická klinika LF MU a FN u sv. Anny v Brně Czech Republic Chlapec3 PSORS1 u1. Trembath RC, et al. Hum Mol Genet. 1997;6(5):813-20. Chromosome 6 MHC 3500 kb 3000 2500 2000 1500 1000 500 0 Class III Class II Class I 6p21.1- 6p21.3 PSORS1 DP DN DM LMP/TAP DO DQ DR C4 C2 HSP70 TNF B C E F G A b b b b b a a a a a a STG CCHCR1 POU5F1 HCG27 SEEK1 HLA-E CDSN SPR1 TCF19 PSORS1C3 ERVK HLA-C HLA-B uIllustration adapted from: Bowcock AM, Krueger JG. Nat Rev Immunol. 2005;5(9):699-711. S1/11 VV-prof16 Nestle FO, Kaplan DH, Barker J.: N Engl J Med. 2009 Jul 30;361(5):496-509 Psoriasis is a Complex Disease Characteristics Inflammatory disorder Various clinical features Lifelong, chronic relapsing disease Plaque-type psoriasis most common form Multigenic predisposition (1% - 3% of Caucasian population affected) Nail psoriasis3 40-50%3 Joints (PsA)2 7-40% ~80% Plaque1 Palmoplantar1 ~4% ~1-2% Pustular1 ~2% Erythrodermic1 ~2-6% Inverse Psoriasis1 ~12% Guttate1 1García-Diez A et al. Dermatology. 2008;216(2):137-151. 2Wilson FC et al. Arthritis Rheum. 2009;61:233-239. 3Griffiths CE et al. Br J Dermatol. 2007;156(2):258-262. #### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! #### ########## Presentation updated on Wednesday, 15 December, 2010 by SILE ########## ########### Presentation updated on Wednesday, 15 December, 2010 ########### Author: SILE Purpose: Optimize slide decks QA: 15-Dec-10 Review By: 24-Jun-11 Review Type: Scientific, Reference Check and Compliance Review Slide: 13/227 Golimumab-Specific Deck: No ########### Presentation 'OPTIMize_Pso_core_24NOV08.ppt' created on Monday, 24 November, 2008 ########### Author: SILE QC&C: 24-Nov-08 Review By: 24-May-09 Medical Review: Yes Slide: 4/131 ########### Presentation 'OPTIMize_Pso_core_14MAY09.ppt' created on Thursday, 14 May, 2009 ########### Author: SILE QC&C: 14-May-09 Review By: 24-Oct-09 Medical Review: Yes Slide: 1/131 TREG Tp APC Monocyt Eosinofil Mast/Basofil Neutrofil Makrofág TH2 TH1 B TC ¨ Ag Senzitizace Vývoj patogenních T-buněk Nerovnováha efektor/ supresor Místní zánět Tkáňové poškození Fibróza I.M.I.D. Alergie Ankylozující Spondylitis Astma Crohnova nemoc Graft Rejection Sclerosis multiplex Psoriasis Psoriatická Artritis Revmatoidní Artritis Sarcoidosis SLE Type I DM Ulcerativní Colitis Uveitis Imunobiologie IMID („immune mediated inflammatory diseases“) Psoriasis Demography Czech Republic Severity % Prevalence 2% mild to moderate 75 153000 moderate to severe 25 51000 severe 15 30600 E:\obraz.06.jpg Podle Gottliebové, 2004 aktivačí signály Self-DNA May Trigger Plasmacytoid Dendritic Cell Activation and Initiate Psoriasis 1 –pDCs use Toll-like receptor (TLR)7 and TLR9 to recognise viral/microbial nucleic acids in endosomal compartments –The antimicrobial peptide LL37, a cathelicidin overexpressed in psoriatic skin, forms an aggregate with self-DNA that binds to TLR9 and activates pDCs –This pathway may drive primary autoimmunity in psoriasis DNA_logo Self DNA DNA_logo LL37 Recognition by pDC TLR9 monocyte LL37/self DNA aggregate pDC u1. Lande R, et al. Nature. 2007; 449:564-9. Zaoblený obdélník: IFN-α burst IFN-α burst S1/50 IL-12 and IL-23 Define the T-helper Environment in Psoriasis1,2 ↑Cytokines including IFN-γ TNF-α IL-2 Th17 Inflammation, keratinocyte hyperplasia, neovascularisation, vasodilatation, T cell/neutrophil influx Plaque formation Naïve T cell uIL-23 dendritic cell DC Th1 Naïve T cell uIL-12 dendritic cell DC ↑Cytokines including IL-17 IL-22 TNF-α S1/39 u1. Gately MK, et al. Annu Rev Immunol. 1998; 16:495-521. 2. Wilson NJ, et al. Nat Immunol. 2007; 8:950-7. T Cells Found in Psoriatic Plaques: Th1 and Th17 1,2 uNo u uIL-4 uLow level uYes uYes uFound in psoriatic plaque6 uIFN-g u u u uSubset uIL-10 uTGF-b uIL-17 uIL-22 uDefining Cytokines3-5 Th2 Th1 Treg Th17 u1. Austin LM, et al. J Invest Dermatol. 1999;113:752-9. 2. Sabat R, et al. Exp Dermatol. 2007;16:779-98. 3. Janeway CA, et al. Immunobiology. 5th ed. New York: Garland; 2001. 4. Wilson NJ, et al. Nat Immunol. 2007;8(9):950-7.5. Kagen MH, et al. Ernst Schering Res Found Workshop. 2006(56):193-209. 6. Lowes MA, et al. J Invest Dermatol. 2008. EPub 2008 Jan 17. S1/26 Th1 Cytokines Drive Inflammatory Processes in the Psoriatic Plaque Activation u u u u u Th1 Cytokine Release Inflammation uKeratinocyte and endothelial cell activation u uNeovascularisation u uT cell influx u uiNOS (NO) uIL-8 uMIG, IP-10 uVEGF uMHC Class II ICAM-1 VCAM-1 u u uNeutrophil influx u uIFN-γ uTNF-α uVasodilation u uAdapted from: Lowes MA, et al. Dermatol Clin. 2004; 22:349-69, vii. S1/27 Th17 Cytokines Drive Inflammation and Keratinocyte Hyperplasia in Psoriatic Plaque u u u u u Th17 Activation uMCP-1 Groα IL-8 uG-CSF uGM-CSF uIL-6 uPGE2 uICAM-1 VCAM-1 u uIL-17A uIL-17F uIL-22 uTNF-α uMonocyte and neutrophil recruitment uNeovascularisation uVasodilatation uT cell influx uKeratinocyte hyperplasia Cytokine Release Inflammation uAggarwal S, Gurney AL. J Leukoc Biol. 2002; 71(1):1-8. S1/28 T-cell Cytokines Stimulate Keratinocyte Hyperplasia 1,2 uDysregulated KC production of growth factors uTGF-a, KGF, amphiregulin, GM-CSF, FGF-10, IL-19, IL-20 Uncontrolled KC proliferation and differentiation Proliferative cell population: x2 Cell cycle time reduction: x8 Daily cell production: x28 uTNF-a uIFN-g uIL-17 uIL-22 Frex_5 frex_09 frex_09 uTh17 uTh17 uTh17 uTh1 uTh1 u1. Albanesi C, et al. Clin Dermatol. 2007; 25:581-8. 2. Weinstein GD et al. J Invest Dermatol. 1985; 85:579-83. S1/29 T Cell Infiltration, Angiogenesis and Epidermal Hyperplasia: the Vicious Cycle of Psoriasis –Dendritic cells, lymphocytes, and keratinocytes interact in a "vicious cycle" to establish and perpetuate the inflammatory phenotype Zaoblený obdélník: Dendritic cell and T cell activation Dendritic cell and T cell activation Zaoblený obdélník: Keratinocyte activation Keratinocyte activation uImage courtesy of of Professor J Prinz. Zaoblený obdélník: Leucocyte recruitment Leucocyte recruitment S1/33 Nickoloff BJ, et al. J Clin Invest. 2004;113(12):1664-75. 004 003 002 004 005 006 007 008 009 010 011 012 013 015 014 016 017 019 020 023 024 024a Fotochemoterapie - PUVA 026 Fotochemoterapie - PUVA 029 030 031 032 035 036 UVB – „Narrow band lamp“ 037 039 040 041 042 043 044 045 046 047 048 049 050 051 052 VV-prof17 Nestle FO, Kaplan DH, Barker J.: N Engl J Med. 2009 Jul 30;361(5):496-509 Tumor Necrosis Factor-Alpha (TNF-a) uA cytokine and major mediator of inflammation. u uPrimarily produced by macrophages, but also by T cells, NK cells and mast cells. u uBoth soluble and membrane-bound forms of TNF-a have biologic activity. Bradley JR. J Pathol. 2008; 214:149-160. Knight DM et al. Mol Immunol. 1993; 30(16):1443-1453. #### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! #### ########## Presentation updated on Friday, 21 May, 2010 by WEBO ########## ########### Presentation updated on Friday, 21 May, 2010 ########### Author: WEBO Purpose: Standard slide decks - MIC QA: 21-May-10 Review By: 01-May-11 Review Type: Scientific, Reference Check and Compliance Review Slide: 6/37 Golimumab-Specific Deck: No ########### Presentation 'REM_SK023_Infliximab MoA_R01.ppt' created on Friday, 16 January, 2009 ########### Author: WEBO QC&C: 16-Jan-09 Review By: 16-Nov-09 Medical Review: Yes Slide: 5/34 The future in the biological treatment →Prognostic biomarkers → →Personalized medicine → →New molecules → →Wide knowledge of genetic background of psoriasis u TNFα TNFa Plays a Central Role in the Pathogenesis of Psoriasis TNF uMultifunctional proinflammatory ucytokine u TNF_Signaling_680 Před léčbou I~000054 Před léčbou I~000056 Před léčbou I~000057 Po 4 týdnech léčby I~000012 Po 4 týdnech léčby I~000014 Po 24 týdnech léčby foto 74 058 Po 24 týdnech léčby foto 74 059 Před léčbou I~000035 Po 4 týdnech léčby I~000005 Po 24 týdnech léčby f 061 foto 70 047 foto 70 045 foto 70 049 foto 70 043 foto 74 047 foto 74 048 foto 74 051 foto 74 053 orlí_1912